Lomitapide for use in methods of treating hyperlipidemia and hypercholesterolemia in pediatric patients

ABSTRACT

Provided herein are methods of treating hyperlipidemia or hypercholesterolemia in pediatric patients with lomitapide or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Application Ser.No. 63/058,211, filed Jul. 29, 2020, the contents of which is herebyincorporated by reference in its entirety for all purposes.

BACKGROUND

Homozygous familial hypercholesterolaemia (HoFH) is a rare andlife-threatening inherited disorder of lipid metabolism with anestimated prevalence of 1 per 160,000 to 300,000 in the Europeanpopulation. The Consensus Panel on Familial Hypercholesterolaemia (FH)of the European Atherosclerosis Society (EAS) recommends the followingcriteria for the diagnosis of HoFH:

-   -   i) genetic confirmation of 2 mutant alleles at the LDL receptor        (LDLR), apolipoprotein B (apo B), proprotein convertase        subtilisin/kexin type 9 (PCSK9), or LDL-receptor adapter protein        1 (LDLRAP1) gene locus or    -   ii) an untreated low-density lipoprotein cholesterol        (LDL-C) >500 mg/dL (13 mmol/L) and treated LDL-C≥300 mg/dL (8        mmol/L), respectively together with either cutaneous or tendon        xanthomas before the age of 10 years or untreated LDL-C levels        consistent with heterozygous FH in both parents.

Significantly elevated LDL-C levels lead to premature, severe, andprogressive atherosclerosis and development of early cardiovasculardisease (CVD). The average age of death is 18 years if untreated andeffective lipid-lowering therapy (LLT) greatly improves survival inHoFH. Based on the evidence that treatment can delay the onset of CVD,primary prevention is suggested to start as early as possible and mainlyconsists of lowering LDL-C levels to <135 mg/dL (<3.5 mmol/L) inpediatric HoFH patients and to <100 mg/dL (<2.5 mmol/L) in adults.Secondary prevention comprises a decrease of LDL-C levels to <70 mg/dL(<1.8 mmol/L) in adults with CVD as recommended by the EAS.

A number of treatments are currently available for lowering serumcholesterol and triglycerides. However, each has its own drawbacks andlimitations in terms of efficacy, side-effects and qualifying patientpopulation.

Thus, there is a need for safe, early and effective treatment ofpediatric patients with HoFH.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean lomitapide pediatric starting dose (mg) based onPBPK modeling and allometric scaling.

FIG. 2 shows the design of the clinical study in Example 2.

SUMMARY

In embodiments, the present disclosure provides, a method of safelyadministering lomitapide, or a pharmaceutically acceptable salt thereof,to a pediatric patient comprising:

-   -   (a) administering a first daily dose of about 0.5 mg to about        2.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient aged 5 to 15 years; and    -   (b) administering a first daily dose of about 2.5 mg to about        7.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient aged 16 to 17 years, wherein the first        daily dose is administered to the patient for about 1 to 4        weeks.

In embodiments, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia in a pediatric patient,comprising:

-   -   (a) administering a first daily dose of about 0.5 mg to about        2.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient's age is 5 to 15 years;    -   (b) administering a first daily dose of about 2.5 mg to about        7.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient's age is 16 to 17 years, wherein the first        daily dose is administered to the patient for about h to 4        weeks.

In embodiments, provided herein is a method of treating hyperlipidemiaor hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 0.5 mg to about 2.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 5 to 10 years, wherein the first daily        dose is administered to the patient for about 1 to 4 weeks.

In embodiments, provided herein is a method of treating hyperlipidemiaor hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 0.5 mg to about 2.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 11 to 15 years, wherein the first daily        dose is administered to the patient for about 1 to 4 weeks.

In embodiments, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 2.5 mg to about 7.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 16 to 17 years, wherein the first daily        dose is administered to the patient for about 1 to 4 weeks.

Definitions

The term “about” when immediately preceding a numerical value means arange (e.g., plus or minus 10% of that value). For example, “about 50”can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc.,unless the context of the disclosure indicates otherwise, or isinconsistent with such an interpretation. For example in a list ofnumerical values such as “about 49, about 50, about 55, . . . ”, “about50” means a range extending to less than half the interval(s) betweenthe preceding and subsequent values, e.g., more than 49.5 to less than50.5. Furthermore, the phrases “less than about” a value or “greaterthan about” a value should be understood in view of the definition ofthe term “about” provided herein. Similarly, the term “about” whenpreceding a series of numerical values or a range of values (e.g.,“about 10, 20, 30” or “about 10-30”) refers, respectively to all valuesin the series, or the endpoints of the range.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference for all purposes in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of this disclosure. This disclosure will govern in the instancethat there is any inconsistency between the patents, patent applicationsand publications cited and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

The terms “administer,” “administering” or “administration” as usedherein refer to either directly administering a compound orpharmaceutically acceptable salt or ester of the compound or acomposition comprising the compound or pharmaceutically acceptable saltor ester of the compound to a patient.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound, or a salt, solvate or ester thereof, that, when administeredto a patient, is capable of performing the intended result. For example,an effective amount of lomitapide is that amount which is required toreduce at least one symptom of HoFH in a patient, e.g. the amountrequired to reduce the patient's low-density lipoprotein cholesterol(LDL-C). The actual amount which comprises the “effective amount” or“therapeutically effective amount” will vary depending on a number ofconditions including, but not limited to, the severity of the disorder,the size and health of the patient, and the route of administration. Askilled medical practitioner can readily determine the appropriateamount using methods known in the medical arts.

The phrase “pediatric patient” as used herein refers to a patient lessthan 18 years of age.

The phrase “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The term “salts” as used herein embraces pharmaceutically acceptablesalts commonly used to form alkali metal salts of free acids and to formaddition salts of free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. The term “salts” alsoincludes solvates of addition salts, such as hydrates, as well aspolymorphs of addition salts. Suitable pharmaceutically acceptable acidaddition salts can be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriateorganic acids can be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonicacids, for example formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid.

The term “treating” as used herein with regard to a patient, refers toimproving at least one symptom of the patient's disorder. Treating canbe improving, or at least partially ameliorating a disorder.

The term “therapeutic effect” as used herein refers to a desired orbeneficial effect provided by the method and/or the composition. Forexample, the method for treating HoFH provides a therapeutic effect whenthe method reduces at least one symptom of HoFH, e.g., reducelow-density lipoprotein cholesterol (LDL-C), in a patient.

DETAILED DESCRIPTION Lomitapide

Lomitapide is a first in class oral, selective inhibitor of microsomaltransfer protein (MTP), an intracellular lipid-transfer protein that isfound in the lumen of the endoplasmic reticulum and is responsible forbinding and shuttling individual lipid molecules between membranes. MTPplays a key role in the assembly of apo B containing lipoproteins in theliver and intestines. Inhibition of MTP reduces lipoprotein secretionand circulating concentrations of lipoprotein-borne lipids includingcholesterol and triglycerides.

The chemical name of lomitapide isN-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide.Its structural formula is:

Lomitapide and other inhibitors of MTP-mediated neutral lipid transferactivity are described, for example, in U.S. Pat. Nos. 5,789,197,5,883,109, 6,066,653, and 6,492,365, each of which is incorporatedherein by reference in its entirety. MTP inhibitors are describedthroughout U.S. Pat. No. 6,066,653, in particular in columns 3-28.Lomitapide and methods for its use are described, for example, in U.S.Pat. Nos. 7,932,268; 8,618,135; 9,265,758; 9,364,470; 9,433,617;9,861,622, 10,016,404, and 10,555,938 each of which is incorporated byreference herein in its entirety. See also U.S. Pat. No. 10,213,419 theentirety of which is incorporated herein by reference.

The European Commission (EC) granted authorization for lomitapide underthe trade name ‘Lojuxta®’ in July 2013. Lomitapide is a “lipid modifyingagent” according to the Anatomical Therapeutic Chemical (ATC)Classification System (ATC code C10AX12). It is indicated as an adjunctto a low-fat diet and other lipid-lowering medicinal products with orwithout LA in adult patients with HoFH. Genetic confirmation of HoFHshould be obtained whenever possible. Other forms of primaryhyperlipoproteinaemia and secondary causes of hypercholesterolaemia(e.g., nephrotic syndrome, hypothyroidism) must be excluded.

However, Lojuxta is not approved in pediatric patients (i.e., inpatients less than 18 years of age) because the safety and efficacy oflomitapide in this sensitive population has not been established.

In formulating the compositions, lomitapide or a pharmaceuticallyacceptable salt thereof, in the amounts described herein, may becompounded according to accepted pharmaceutical practice with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in the particular type of unitdosage form. Such dosage forms can be administered to the patient on aregimen of one to four doses per day.

In one aspect, the disclosure provides tablets containing a lomitapidecomposition as described herein. A tablet may be made by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared using binder (for example, gelatin,microcrystalline cellulose, or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art. Thedisclosed excipients may serve more than one function. For example,fillers or binders may also be disintegrants, glidants, anti-adherents,lubricants, sweeteners and the like.

Liquid formulations can also be prepared by dissolving or suspending oneor the combination of active substances in a conventional liquid vehicleacceptable for pharmaceutical administration so as to provide thedesired dosage in one to four teaspoonsfuls.

Dosage units including tablets, capsules and caplets, of various sizescan be prepared, e.g., of about 2 to 10000 mg in total weight,containing one or both of the active substances in the ranges describedabove, with the remainder being a physiologically acceptable carrier ofother materials according to accepted pharmaceutical practice. Thesetablets can, of course, be scored to provide for fractional doses.Gelatin capsules can be similarly formulated. For example, in someembodiments a scored tablet may provide the dosage unit. Under thedirection of a physician or other medical professional, the subject maybe directed to take one portion of the dosage unit, wherein the oneportion will provide the desired dosage level for given interval. At thefollowing interval, the patient may be instructed to take two or moreportions of the dosage unit wherein the two or more portions willprovide the desired dosage level for that interval.

Formulations of lomitapide are commercially available, for example, asJuxtapid capsules. Each Juxtapid capsule contains lomitapide mesylateequivalent to 5, 10, 20, or 30 mg lomitapide free base and the followinginactive ingredients: pregelatinized starch, sodium starch glycolate,microcrystalline cellulose, lactose monohydrate, silicon dioxide andmagnesium stearate. The capsule shells of all strengths contain gelatinand titanium dioxide; the 5 mg, 10 mg and 30 mg capsules also containred iron oxide; and the 30 mg capsules also contain yellow iron oxide.The imprinting ink contains shellac, black iron oxide, and propyleneglycol. However, the scope of the present disclosure is not limited todosage strengths of Juxtapid presently available commercially, andincludes capsules containing lomitapide mesylate (or otherpharmaceutically acceptable salts of lomitapide) equivalent to 5, 10,20, 30, 40, or 60 mg lomitapide free base.

Methods of the Present Disclosure

The present disclosure provides methods of safely administeringlomitapide to pediatric HoFH patients. It will be understood that inembodiments of the methods provided herein, the patient is a human.

The disclosure provides methods for treating hyperlipidemia orhypercholesterolemia (e.g., Homozygous Familial Hypercholesterolaemia(HoFH)) by administering an effective and tolerable amount of lomitapideor a pharmaceutically acceptable salt thereof, to a pediatric patient inneed thereof. An effective amount is an amount sufficient significantlyreduce hyperlipidemia or hypercholesterolemia (e.g., HoFH) symptoms orto alleviate those symptoms. Formulations employed in the presentmethods can incorporate lomitapide or a pharmaceutically acceptable saltthereof into a formulation such that the formulation providestherapeutically effective blood plasma levels of lomitapide or apharmaceutically acceptable salt thereof for the treatment ofhyperlipidemia or hypercholesterolemia (e.g., HoFH).

In some embodiments, a therapeutically effective dose is achieved bystarting the patient on an initial daily dose and titrating to anefficacious and tolerated dose by gradually modifying (e.g., increasingor decreasing) the daily administered amount of lomitapide or apharmaceutically acceptable salt thereof until a dose that is effectiveand tolerated is achieved (e.g., the patient with hyperlipidemia orhypercholesterolemia (Homozygous Familial Hypercholesterolaemia (HoFH))is treated). In some embodiments, the efficacious dose is a dose thatimproves at least one symptom of the patient's Homozygous FamilialHypercholesterolaemia (HoFH), or hyperlipidemia or hypercholesterolemia.In some embodiments, the efficacious dose is a dose that reduces thepatient's LDL-C to <135 mg/dL (3.5 mmol/L).

In some embodiments, the lomitapide or a pharmaceutically acceptablesalt thereof is administered in escalating doses. In some embodiments,the escalating doses comprise at least a first dose level and a seconddose level. In some embodiments, the escalating doses comprise at leasta first dose level, a second dose level, and a third dose level. In someembodiments, the escalating doses further comprise a fourth dose level.In some embodiments, the escalating doses further comprise a fifth doselevel. In some embodiments, the escalating doses comprise a first doselevel, a second dose level, a third dose level, a fourth dose level anda fifth dose level. In some embodiments, six, seven, eight, nine and tendose levels are contemplated.

In some embodiments, each dose level is no more than 60% of theimmediately following dose level. In embodiments, each dose level is nomore than 50% of the immediately following dose level. In embodiments,each dose level is no more than 40% of the immediately following doselevel. In some embodiments, each dose level is no more than 33% of theimmediately following dose level. In some embodiments, each dose levelis no more than 20% of the immediately following dose level. In someembodiments, dose levels are separated by 12 log units. In someembodiments, dose levels are separated by 1 log unit.

In one aspect, the present disclosure provides a method of safelyadministering lomitapide, or a pharmaceutically acceptable salt thereof,to a pediatric patient comprising:

-   -   (a) administering a first daily dose of about 0.5 mg to about        2.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient aged 5 to 15 years; and    -   (b) administering a first daily dose of about 2.5 mg to about        7.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient aged 16 to 17 years, wherein the first        daily dose is administered to the patient for about 1 to 4        weeks.

In some embodiments, the method of safely administering lomitapide, or apharmaceutically acceptable salt thereof, to a pediatric patientcomprises administering a first daily dose of about 2 mg of lomitapide,or a pharmaceutically acceptable salt thereof to a patient aged 5 to 15years.

In some embodiments, the method of safely administering lomitapide, or apharmaceutically acceptable salt thereof, to a pediatric patientcomprises administering a first daily dose of about 5 mg of lomitapide,or a pharmaceutically acceptable salt thereof to a patient aged 16 to 17years.

In one aspect, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia in a pediatric patient,comprising:

-   -   (a) administering a first daily dose of about 0.5 mg to about        2.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient's age is 5 to 15 years;    -   (b) administering a first daily dose of about 2.5 mg to about        7.5 mg of lomitapide, or a pharmaceutically acceptable salt        thereof to a patient's age is 16 to 17 years,    -   wherein the first daily dose is administered to the patient for        about 1 to 4 weeks.

In some embodiments, the method of treating hyperlipidemia orhypercholesterolemia in a pediatric patient comprises administering afirst daily dose of about 2 mg of lomitapide, or a pharmaceuticallyacceptable salt thereof to a patient aged 5 to 15 years.

In some embodiments, the method of treating hyperlipidemia orhypercholesterolemia in a pediatric patient comprises administering afirst daily dose of about 5 mg of lomitapide, or a pharmaceuticallyacceptable salt thereof to a patient aged 16 to 17 years.

In one aspect, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 0.5 mg to about 2.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 5 to 10 years, wherein the first daily        dose is adminstered to the patient for about 1 to 4 weeks.

In one aspect, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 0.5 mg to about 2.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 11 to 15 years, wherein the first daily        dose is administered to the patient for about 1 to 4 weeks.

In one aspect, the present disclosure provides a method of treatinghyperlipidemia or hypercholesterolemia, comprising:

-   -   administering a first daily dose of about 2.5 mg to about 7.5 mg        of lomitapide, or a pharmaceutically acceptable salt thereof to        a pediatric patient age 16 to 17 years, wherein the first daily        dose is adminstered to the patient for about 1 to 4 weeks.

In some embodiments, the first daily dose is administered to the patientfor about 4 weeks. In embodiments, the first daily dose is administeredfor about 1 week to about 6 weeks, including about 1 week, about 2weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks,including all values and subranges therebetween.

In some embodiments each dose level of lomitapide or a pharmaceuticallyacceptable salt thereof is administered to the subject for from 2 daysto 30 weeks, or more. In some embodiments each dose level isadministered to the subject for from about 1 week to about 12 weeks. Insome embodiments, each dose level is administered to the subject forabout 1 week to about 5 weeks. In some embodiments each dose level isadministered to the subject from about 1 to about 4 weeks. In someembodiments each dose level is administered to the subject from about 1to about 3 weeks. In some embodiments each dose level is administered tothe subject from about 1 to about 2 weeks.

In some embodiments, lomitapide or a pharmaceutically acceptable salt isadministered. In some embodiments, lomitapide mesylate is administered.In some embodiments, lomitapide or a pharmaceutically acceptable saltthereof is administered orally.

In some embodiments, lomitapide or a pharmaceutically acceptable saltthereof is administered in a daily dose of about 0.1 mg to about 100 mgto a pediatric patients with hyperlipidemia or hypercholesterolemia(Homozygous Familial Hypercholesterolaemia (HoFH)) in need thereof,including about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about0.5 mg, about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 7.5 mg,about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about90 mg, about 95 mg to about 100 mg, including any subrange or valuetherebetween. In some embodiments, about 2 mg to about 60 mg oflomitapide or a pharmaceutically acceptable salt thereof is administeredon a daily basis. In some embodiments, about 2 mg to about 20 mg oflomitapide or a pharmaceutically acceptable salt thereof is administeredon a daily basis. In some embodiments, about 2 mg to about 40 mg oflomitapide or a pharmaceutically acceptable salt thereof is administeredon a daily basis.

In some embodiments, the pediatric patient in need of hyperlipidemia orhypercholesterolemia (e.g., Homozygous Familial Hypercholesterolaemia(HoFH)) treatment is administered a daily dose of 2 mg of lomitapide ora pharmaceutically acceptable salt thereof in the first dosing period, adaily dose of 2 mg of lomitapide or a pharmaceutically acceptable saltthereof in the second dosing period, and a daily dose of 5 mg oflomitapide or a pharmaceutically acceptable salt thereof in the thirddosing period, a daily dose of 10 mg of lomitapide or a pharmaceuticallyacceptable salt thereof in the fourth dosing period, and a daily dose of20 mg of lomitapide or a pharmaceutically acceptable salt thereof in thefifth dosing period.

In some embodiments, the pediatric patient in need of hyperlipidemia orhypercholesterolemia (e.g., Homozygous Familial Hypercholesterolaemia(HoFH)) treatment is administered a daily dose of 2 mg of lomitapide ora pharmaceutically acceptable salt thereof in the first dosing period, adaily dose of 5 mg of lomitapide or a pharmaceutically acceptable saltthereof in the second dosing period, and a daily dose of 10 mg oflomitapide or a pharmaceutically acceptable salt thereof in the thirddosing period, a daily dose of 20 mg of lomitapide or a pharmaceuticallyacceptable salt thereof in the fourth dosing period, and a daily dose of40 mg of lomitapide or a pharmaceutically acceptable salt thereof in thefifth dosing period.

In some embodiments, the pediatric patient in need of hyperlipidemia orhypercholesterolemia (e.g., Homozygous Familial Hypercholesterolaemia(HoFH)) treatment is administered a daily dose of 5 mg of lomitapide ora pharmaceutically acceptable salt thereof in the first dosing period, adaily dose of 10 mg of lomitapide or a pharmaceutically acceptable saltthereof in the second dosing period, and a daily dose of 20 mg oflomitapide or a pharmaceutically acceptable salt thereof in the thirddosing period, a daily dose of 40 mg of lomitapide or a pharmaceuticallyacceptable salt thereof in the fourth dosing period, and a daily dose of60 mg of lomitapide or a pharmaceutically acceptable salt thereof in thefifth dosing period.

In some embodiments, the first dosing period, second dosing period, orthird dosing period is about or at least about 1-8 weeks, includingabout or at least about 1 week, about or at least about 2 weeks, aboutor at least about 3 weeks, about or at least about 4 weeks, about or atleast about 5 weeks, about or at least about 6 weeks, about or at leastabout 7 weeks, or about or at least about 8 weeks, including allsubranges and values therebetween.

In some embodiments, the patient's age is from 5 to 10 years, from 11 to15 years, or from 16 to 17 years.

In some embodiments of any of the methods disclosed herein, thelomitapide is provided to the patient as an adjunct to a low-fat dietand other lipid-lowering treatments, including LDL apheresis. In someembodiments, concomitant lipid-lowering treatments include one or moreof the following: statins, ezetimibe, nicotinic acid, bile acidsequestrant, fibrate, and apheresis.

In some embodiments, the low-fat diet comprises a diet wherein less thanabout 30% of patient's total calories are from fat, less than about 20%of patient's total calories are from fat, less than about 15% ofpatient's total calories are from fat, or less than about 10% ofpatient's total calories are from fat. In some embodiments, the low-fatdiet comprises a diet wherein less than about 20% of patient's totalcalories are from fat.

In some embodiments, patients receiving lipid lowering therapies duringtreatment with lomitapide are administered dietary supplements thatprovided approximately 400 international units vitamin E, 210 mgalpha-linolenic acid (ALA), 200 mg linoleic acid, 110 mgeicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) perday.

In some embodiments of any of the methods disclosed herein,administration of lomitapide to a pediatric patient reduces one or moreof the following: low-density lipoprotein cholesterol (LDL-C), totalcholesterol (TC), apolipoprotein B (apo B), and non-high densitylipoprotein cholesterol (non-HDL-C) in patients with homozygous familialhypercholesterolemia (HoFH). In some embodiments, the lomitapide isprovided to the patient as an adjunct to a low-fat diet and otherlipid-lowering treatments, including LDL apheresis.

In some embodiments, administration of lomitapide to a pediatric patientreduces one or more of the following: low-density lipoproteincholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B),and non-high density lipoprotein cholesterol (non-HDL-C) in patientswith homozygous familial hypercholesterolemia (HoFH).

In some embodiments, administration of lomitapide to a pediatric patientas an adjunct to a low-fat diet and other lipid-lowering treatments(e.g., as disclosed herein) according to any of the methods disclosedherein reduces one or more of the following: low-density lipoproteincholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B),and non-high density lipoprotein cholesterol (non-HDL-C) by about or atleast about 10% to about or at least about 90% or more, including aboutor at least about 10%, about or at least about 20%, about or at leastabout 30%, about or at least about 40%, about or at least about 50%,about or at least about 60%, about or at least about 70%, about or atleast about 80%, about or at least about 90%, or more, including allvalues and subranges therebetween.

In embodiments of any of the methods disclosed herein, the maximum dosein a pediatric patient with Child-Pugh A aged from 5 to 10 years is 10mg.

In embodiments of any of the methods disclosed herein, the maximum dosein a pediatric patient with Child-Pugh A aged from 11 to 15 years is 20mg.

In embodiments of any of the methods disclosed herein, the maximum dosein a pediatric patient with Child-Pugh A aged from 11 to 15 years is 40mg.

In some embodiments, the patient's age is from 5 to 10 years and thedaily dose of lomitapide in the first dosing period is 2 mg, the dailydose of lomitapide in the second dosing period is 2 mg, and the dailydose of lomitapide in the third dosing period is 5 mg, the daily dose oflomitapide in the fourth dosing period is 10 mg. In some embodiments,the first dosing period is about or at least about 4 weeks, the seconddosing period is about or at least about 4 weeks, and the third dosingperiod is about or at least about 4 weeks, the fourth dosing period isabout or at least about 4 weeks, and the fifth dosing period is about orat least about 4 weeks. In some embodiments, the first, second, third,fourth, and fifth dosing periods are each about 4 weeks±3 days.

In some embodiments, the patient's age is from 11 to 15 years and thedaily dose of lomitapide in the first dosing period is 2 mg, the dailydose of lomitapide in the second dosing period is 5 mg, the daily doseof lomitapide in the third dosing period is 10 mg, the daily dose oflomitapide is about 20 mg in the fourth dosing period, the daily dose isabout 40 mg in the fifth dosing period. In some embodiments, the firstdosing period is about or at least about 4 weeks, the second dosingperiod is about or at least about 4 weeks, and the third dosing periodis about or at least about 4 weeks, the fourth dosing period is about orat least about 4 weeks, and the fifth dosing period is about and atleast about 4 weeks. In some embodiments, the first, second, third,fourth, and fifth dosing periods are each about 4 weeks±3 days.

In some embodiments, the patient's age is 16 to 17 years and the dailydose of lomitapide in the first dosing period is about 5 mg, the dailydose of lomitapide in the second dosing period is about 10 mg, the dailydose of lomitapide in the third dosing period is about 20 mg, the dailydose of lomitapide in the fourth dosing period is about 40 mg, and thedaily dose of lomitapide in the fifth dosing period is about 60 mg. Insome embodiments, the first dosing period is about or at least about 4weeks, the second dosing period is about or at least about 4 weeks, andthe third dosing period is about or at least about 4 weeks, the fourthdosing period is about or at least about 4 weeks, and the fifth dosingperiod is about or at least about 4 weeks. In some embodiments, thefirst, second, third, fourth, and fifth dosing periods are each about 4weeks±3 days.

In some embodiments the daily dose is administered as a single dose ordivided into 2 or 3 equal or unequal doses. In some embodiments, thelomitapide is administered once-daily at bedtime.

In some embodiments, lomitapide mesylate in an amount equivalent toabout 2-60 mg of the lomitapide free base is administered. In someembodiments, lomitapide mesylate in an amount equivalent to about 2 mgof the lomitapide free base is administered. In some embodiments,lomitapide mesylate in an amount equivalent to about 2.5 mg of thelomitapide free base is administered. In some embodiments, lomitapidemesylate in an amount equivalent to about 5 mg of the lomitapide freebase is administered. In some embodiments, lomitapide mesylate in anamount equivalent to about 10 mg of the lomitapide free base isadministered. In some embodiments, lomitapide mesylate in an amountequivalent to about 30 mg of the lomitapide free base is administered.In some embodiments, lomitapide mesylate in an amount equivalent toabout 40 mg of the lomitapide free base is administered. In someembodiments, lomitapide mesylate in an amount equivalent to about 60 mgof the lomitapide free base is administered.

In some embodiments, the patient has homozygous familialhypercholesterolemia.

Kits

In some embodiments, the present disclosure provides kits for use intreating hyperlipidemia or hypercholesterolemia (e.g., HomozygousFamilial Hypercholesterolaemia (HoFH)) in a patient in need thereof.Such kits comprise lomitapide or a pharmaceutically salt thereof. Thekits of the present disclosure may be used for administering lomitapideor a pharmaceutically acceptable salt thereof at different dosageintervals, or for titrating the dose of lomitapide or a pharmaceuticallyacceptable salt thereof according to methods described herein. Forexample, the present disclosure provides kits for treatinghyperlipidemia or hypercholesterolemia (e.g., Homozygous FamilialHypercholesterolaemia (HoFH)) in a pediatric subject, comprising atleast three sets of pharmaceutical dosage units; and instructions foruse.

In some embodiments, the kits of the present disclosure may comprisedirections for administration. For example, the kit can includeinstructions to administer lomitapide or a pharmaceutically acceptablesalt thereof in a suitable manner to perform the methods describedherein, e.g., in a suitable dose, dosage form, dosing intervals (e.g.,as described herein). In some embodiments, the informational materialcan include instructions to administer the lomitapide or apharmaceutically acceptable salt thereof to a pediatric patient withhyperlipidemia or hypercholesterolemia (e.g., Homozygous FamilialHypercholesterolaemia (HoFH)).

The kit can include one or more containers for lomitapide or apharmaceutically salt thereof as described herein. In some embodiments,the kit contains separate containers, dividers or compartments for thecomposition and informational material. For example, the composition canbe contained in a bottle, vial, or syringe. In some embodiments, theseparate elements of the kit are contained within a single, undividedcontainer. For example, the composition is contained in a bottle, vialor syringe that has attached thereto the informational material in theform of a label. In some embodiments, the kit includes a plurality(e.g., a pack) of individual containers, each containing one or moreunit dosage forms (e.g., a dosage form described herein) of acomposition described herein. For example, the kit can include aplurality of syringes, ampules, or foil packets each containing a singleunit dose of a composition described herein. An example of such a kit isa blister pack, as typically used for the packaging of tablets, capsulesand the like. The containers of the kits can be air tight, waterproof(e.g., impermeable to changes in moisture or evaporation), and/orlight-tight.

In some embodiments, provided herein is a kit for safely administeringlomitapide, or a pharmaceutically acceptable salt thereof, to apediatric patient aged 5 to 15 comprising: a first daily dose of about0.5 mg to about 2.5 mg of lomitapide, or a pharmaceutically acceptablesalt thereof.

In some embodiments, provided herein is a kit for safely administeringlomitapide, or a pharmaceutically acceptable salt thereof, to apediatric patient aged 16 to 17 years, comprising a first daily dose ofabout 2.5 mg to about 7.5 mg of lomitapide, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, provided herein is a kit for treatinghyperlipidemia or hypercholesterolemia (e.g., homozygous familialhypercholesterolemia) in a pediatric patient aged 5 to 15 yearscomprising: a first daily dose of about 0.5 mg to about 2.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a kit for treatinghyperlipidemia or hypercholesterolemia (e.g., homozygous familialhypercholesterolemia) in a pediatric patient aged 16 to 17 years,comprising a first daily dose of about 2.5 mg to about 7.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a kit for treatinghyperlipidemia or hypercholesterolemia (e.g., homozygous familialhypercholesterolemia) in a pediatric patient aged 5 to 10 yearscomprising: a first daily dose of about 0.5 mg to about 2.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a kit for treatinghyperlipidemia or hypercholesterolemia (e.g., homozygous familialhypercholesterolemia) in a pediatric patient aged 11 to 15 yearscomprising: a first daily dose of about 0.5 mg to about 2.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a kit for treatinghyperlipidemia or hypercholesterolemia in a pediatric patient aged 16 to17 years comprising a first daily dose of about 2.5 mg to about 7.5 mgof lomitapide, or a pharmaceutically acceptable salt thereof.

In some embodiments of the kits provided herein, the kit contains afirst daily dose to be administered to the pediatric patient for about 1to 4 weeks, including about 1 week, about 2 weeks, about 3 weeks andabout 4 weeks. In some embodiments, the kit contains a first daily doseto be administered to the pediatric patient for about 4 weeks.

In some embodiments of the kits provided herein for treatinghyperlipidemia or hypercholesterolemia (e.g., Homozygous FamilialHypercholesterolaemia (HoFH)) in a pediatric patient, the kit contains adaily dose of 2 mg of lomitapide or a pharmaceutically acceptable saltthereof to be administered in a first dosing period, a daily dose of 2mg of lomitapide or a pharmaceutically acceptable salt thereof to beadministered in a second dosing period, a daily dose of 5 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a third dosing period, a daily dose of 10 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fourth dosing period, and a daily dose of 20 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fifth dosing period.

In some embodiments of the kits provided herein for treatinghyperlipidemia or hypercholesterolemia (e.g., Homozygous FamilialHypercholesterolaemia (HoFH)) in a pediatric patient, the kit contains adaily dose of 2 mg of lomitapide or a pharmaceutically acceptable saltthereof to be administered in a first dosing period, a daily dose of 5mg of lomitapide or a pharmaceutically acceptable salt thereof to beadministered in a second dosing period, a daily dose of 10 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a third dosing period, a daily dose of 20 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fourth dosing period, and a daily dose of 40 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fifth dosing period.

In some embodiments of the kits provided herein for treatinghyperlipidemia or hypercholesterolemia (e.g., Homozygous FamilialHypercholesterolaemia (HoFH)) in a pediatric patient, the kit contains adaily dose of 5 mg of lomitapide or a pharmaceutically acceptable saltthereof to be administered in a first dosing period, a daily dose of 10mg of lomitapide or a pharmaceutically acceptable salt thereof to beadministered in a second dosing period, a daily dose of 20 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a third dosing period, a daily dose of 40 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fourth dosing period, and a daily dose of 60 mg oflomitapide or a pharmaceutically acceptable salt thereof to beadministered in a fifth dosing period.

In embodiments of any of the kits disclosed herein, the kit may compriselomitapide dosage units for administration to a pediatric patient agedabout 5-10 years, or about 11-15 years, or about 16 to ≤17 years.

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 5-10 years,wherein the dosage units are shown in the Table below. In someembodiments, when the pediatric patient aged about 5-10 years isclassified as Child-Pugh A, then the maximum dose is 10 mg.

Week Lomitapide Daily Dose (mg) 1 2 4 +/− 2 3 days 8 +/− 5 3 days 12 +/−10 3 days 16 +/− 20 3 days

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 5-10 years,wherein the dosage units are shown in the Table below.

Week Lomitapide Daily Dose (mg) 1 2 4 +/− 2 3 days 8 +/− 5 3 days 12 +/−10 3 days 16 +/− 10 3 days

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 11-15 years,wherein the dosage units are shown in the Table below. In someembodiments, when the pediatric patient aged about 11-15 years isclassified as Child-Pugh A, then the maximum dose is 20 mg.

Week Lomitapide Daily Dose (mg) 1 2 4 +/− 5 3 days 8 +/− 10 3 days 12+/− 20 3 days 16 +/− 40 3 days

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 11-15 years,wherein the dosage units are shown in the Table below.

Week Lomitapide Daily Dose (mg) 1 2 4 +/− 5 3 days 8 +/− 10 3 days 12+/− 20 3 days 16 +/− 20 3 days

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 16 to ≤17years, wherein the dosage units are shown in the Table below. In someembodiments, when the pediatric patient aged about 16 to ≤17 years isclassified as Child-Pugh A, then the maximum dose is 40 mg.

Week Lomitapide Daily Dose (mg) 1 5 4 +/− 10 3 days 8 +/− 20 3 days 12+/− 40 3 days 16 +/− 60 3 days

In some embodiments, the present disclosure provides a kit for use inany one of the methods disclosed herein, comprising lomitapide dosageunits to be administered to a pediatric patient aged about 16 to ≤17years, wherein the dosage units are shown in the Table below.

Week Lomitapide Daily Dose (mg) 1 5 4 +/− 10 3 days 8 +/− 20 3 days 12+/− 40 3 days 16 +/− 40 3 days

The following non-limiting examples illustrate various aspects of thepresent invention.

EXAMPLES Example 1

The objective of this study was to use determine pediatric startingdoses for different age ranges that yield systemic exposures that aresimilar to those achieved in adults aged 18-55 following a 5 mg oraldose using allometric scaling and physiologically-based (PBPK) modelingand simulation approaches.

Method for Allometric Scaling Approach

The first allometric scaling approach for oral clearance in pediatricsis based on the PK relationship:

AUCsteady state=Daily Dose/(CL/F).

Therefore, AUC_(steady state), adults=DailyDose_(adults)/(CL/F)_(adults). AUC_(steady state), pediatrics=DailyDose_(pediatrics)/(CL/F) _(pediatrics). To enable AUC_(steady state),adults=AUC_(steady state, pediatrics), DailyDose_(adults)/(CL/F)_(adults)=Daily Dose_(pediatrics)/(CL/F)_(pediatrics). Then Daily Dose _(pediatrics)=Daily Dose_(adults)*[(CL/F)pediatrics/(CL/F)_(adults)]. From this equation, it can be seen that therequired daily dose in pediatrics is a function of adult dose, adultoral clearance and pediatric oral clearance.

Allometric scaling approach for oral clearance (CL/F) was determinedusing the following equation

? ?indicates text missing or illegible when filed

Method for PBPK Modelling

For the PBPK modeling approach, Simcyp population-based simulator(version 12.2) was used to select the doses for pediatrics age groupsthat will achieve 80-125% AUC_(geometric mean) and Cmax_(geometric mean) in pediatric subjects (2-18 year old, 50% male)compared to mean AUC and Cmax in adults after 5 mg oral dosing (18-55year old, 50% male). 10 trials were simulated with 20 virtual healthysubjects (adults or children) in each trial. The point estimate and 95%confidence interval around the AUC _(geometric mean) and Cmax_(geometric mean) were compared between different doses. The followingstatistics were adopted in the analysis: 1) Null hypothesis: pointestimates of geometric means for AUC and Cmax between children andadults differ more than 20%, i.e., they are not equivalent (note thatthe alternative hypothesis is that the point estimates of geometricmeans for AUC and Cmax in children and adults are equivalent; 2)Statistical test: two-tailed t-test, P=0.05; 3) Variance criteria: 95%confidence interval around the AUCgeometric mean and Cmax,geometricmean, 0.8-1.25 limits. Simcyp estimated human jejunum permeability basedon lomitapide physicochemical properties (Peff,man=9.55*10-4 cm/s) wasused, which allows for Qgut estimation for each age group that accountsfor age-dependent blood flow in intestinal villi that reflectsage-dependent cardiac output (14). In the adult group, the estimatedQgut (15.6 L/hr) is similar to previously used fixed Qgut input (17.9L/hr). The major assumptions made in the model used for simulationswere: 1) The fraction of dose absorbed into enterocytes (F(a)) is thesame between adults and pediatrics; 2) CYP3A4 accounts for 100% oflomitapide metabolism (elimination) in both children and adults.

Results

By comparing the calculated doses using both physiologically-basedpharmacokinetic (PBPK) modeling and allometric scaling approaches (FIG.2 ), the first-in-pediatric doses above 5 years old shown in the tablebelow were proposed.

Age groups Suggested starting dose (mg)  5-10 2 11-15 2 16-18 5

Example 2

This clinical study is a single-arm, open-label, international,multi-center study to evaluate the efficacy and safety of lomitapide inpediatric patients with Homozygous Familial Hypercholesterolaemia (HoFH)on stable lipid-lowering therapy.

The efficacy of lomitapide is measured by the percent change inlow-density lipoprotein cholesterol (LDL-C) at the maximum tolerateddose (MTD) at Week 24±3 days compared to Baseline, when added to stablelipid-lowering therapy (LLT, including lipoprotein apheresis [LA] whereapplicable) in pediatric patients (5 to ≤17 years of age) with HoFH.

The efficacy of lomitapide in pediatric HoFH patients is also assessedby:

Percent change from Baseline at Week 24±3 days in lipid parameters,including total cholesterol (TC), non high-density lipoproteincholesterol (Non-HDL-C), very low-density lipoprotein cholesterol(VLDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoproteinB (apo B);

Percent change from Baseline in TC, non-HDL-C, LDL-C, TG, VLDL-C, Lp(a),and apo B at all other time-points through Week 104±1 week;

Change in LLT and LA from Week 24±3 days through Week 104±1 week; and

Number (percent) of pediatric HoFH patients achieving the EuropeanAtherosclerosis Society (EAS) recommended target LDL-C of <135 mg/dL(3.5 mmol/L) at Week 24±3 days and at any time on study.

Abbreviations:

Term or Abbreviation Description AE Adverse event ALA Alpha-linolenicacid ALT Alanine transaminase AP Alkaline phosphatase apo A-IApolipoprotein A-I apo B Apolipoprotein B ASCVD Atheroscleroticcardiovascular disease AST Aspartate transaminase ATC AnatomicalTherapeutic Chemical BMI Body mass index BG Blood glucose BSA Bodysurface area BUN Blood urea nitrogen CBC Complete blood count CKCreatinine kinase C_(max) Maximum concentration CVD Cardiovasculardisease CYP Cytochrome P 450 DHA Docosahexaenoic acid EAS EuropeanAtherosclerosis Society ECG Electrocardiogram eCRF Electronic CaseReport Form EFA Essential fatty acids EMA European Medicines Agency EPAEicosapentaenoic acid EoT End of Treatment FDA Food and DrugAdministration FH Familial Hypercholesterolaemia GGT Gamma-glutamyltransferase GFR Glomerular filtration rate HBsAg Hepatitis B surfaceantigen Anti-HBc Antibody to Hepatitis C HDL-C High-density lipoproteincholesterol HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A HoFHHomozygous familial hypercholesterolaemia IU International units LALipoprotein apheresis LDL Low-density lipoprotein LDL-C Low-densitylipoprotein cholesterol (conventional mg/dL units can be converted to SI[mmol/L] units using the factor 0.0259) LDLR LDL receptor LDLRAP1LDL-receptor adapter protein 1 LLT Lipid-lowering therapy (including LA,where applicable) Lp(a) Lipoprotein a LTE Long-term extension MTDMaximum tolerated dose MTP Microsomal triglyceride transfer proteinNon-HDL-C Non-high-density lipoprotein cholesterol NYHA New York HeartAssociation PCSK9 Proprotein convertase subtilisin/kexin type 9 PKPharmacokinetics SmPC Summary of Product Characteristics TC Totalcholesterol TG Triglycerides ULN Upper limit of normal VLDL-C Very lowdensity lipoprotein cholesterol WHO World Health Organization MTDMaximum tolerated dose MTP Microsomal triglyceride transfer proteinNon-HDL-C Non-high-density lipoprotein cholesterol NYHA New York HeartAssociation PCSK9 Proprotein convertase subtilisin/kexin type 9 PKPharmacokinetics SmPC Summary of Product Characteristics TC Totalcholesterol TG Triglycerides ULN Upper limit of normal VLDL-C Very lowdensity lipoprotein cholesterol WHO World Health Organization

Inclusion Criteria:

Patients eligible for participation include all of the followingcriteria:

-   -   1. Male and female patients aged 5 to ≤17 years with HoFH as        defined by any of the following criteria recommended by the        Consensus Panel on Familial Hypercholesterolaemia of the EAS        (Cuchel, Bruckert et al. 2014):        -   Genetic confirmation of 2 mutant alleles at the LDLR, apo B,            PCSK9, or LDLRAP1 gene locus OR        -   An untreated LDL-C >500 mg/dL (13 mmol/L) or treated LDL-C            ≥300 mg/dL (8 mmol/L) together with either            -   Cutaneous or tendon xanthoma before age 10 years or            -   Untreated LDL-C levels consistent with heterozygous FH                in both parents    -   2. Baseline LDL-C on LLT (Cmax of LDL-C immediately prior to LA,        if applicable)        -   >160 mg/dL (4.1 mmol/L, no documented CVD) or        -   >130 mg/dL (3.4 mmol/L, established CVD defined as aortic            valve disease and/or coronary atherosclerosis)    -   3. Body weight≥15 kg or BMI and height both >10^(th) percentile        according to WHO Growth Charts for Boys and Girls 5 to 19 Years        of Age (see WHO Growth Charts)    -   4. Patient and/or his/her legal representative are informed,        have read and understood the patient information/informed        consent form, and have given written informed assent/consent    -   5. Patient and/or his/her legal representative follow study        procedures and instructions, particularly that        -   LLT (including LA when applicable) is stable for at least 6            weeks prior to Baseline (Run-in Period) and remains stable            through Week 24±3 days (end of Efficacy Phase)        -   The patient is compliant with both the low-fat diet            supplying <20% of energy (calories) from fat or <30 g fat,            whichever is the lesser amount starting at the beginning of            the Run-in Period and the dietary supplement regimen            starting at Week −2 of the Run-in Period, both continuing            until completion of the study (and the LTE of this study,            when applicable)    -   6. Postmenarchal female adolescents use an effective form of        birth control with failure rates <1% per year (e.g., implant,        injectable, combined oral contraceptive, intrauterine        contraceptive device, sexual abstinence, vasectomy or        vasectomised partner) during participation in the study (and at        least 4 weeks thereafter). Patients taking oestrogen-based oral        contraceptives are advised about possible loss of effectiveness        due to diarrhea and/or vomiting. Additional contraceptive        measures are used for 7 days after resolution of symptoms.    -   7. Patient must be in stable physical and mental health at        screening

Exclusion Criteria:

Patients are not included if any of the following criteria apply:

-   -   1. Other forms of primary hyperlipoproteinaemia and secondary        causes of hypercholesterolaemia (e.g., nephrotic syndrome,        hypothyroidism)    -   2. Contraindications for the use of lomitapide according to        section 4.3 of the EMA Summary of Product Characteristics        (SmPC), such as hypersensitivity to the active substance or to        any of the excipients listed in Section 6.1 of the SmPC, known        significant or chronic inflammatory bowel disease or        malabsorption    -   3. Moderate (Child-Pugh B) or severe hepatic impairment        (Child-Pugh C), active liver disease and/or abnormal liver        function tests at screening (AST or ALT >1.5×ULN and/or total        bilirubin >1.5×ULN in the absence of Gilbert's syndrome or        AP >1.5×ULN [based on appropriate age and gender normal values])    -   4. Serum CK >2×ULN    -   5. Chronic renal insufficiency with glomerular filtration rate        (GFR)<70 mL/min/1.73 m² calculated using the Schwartz formula    -   6. Uncontrolled hypertension (defined as mean systolic and/or        diastolic blood pressure        -   ≥95% of normal for age and sex) despite medical therapy    -   7. New York Heart Association (NYHA) Class III or IV congestive        heart failure    -   8. Precocious/delayed puberty or endocrine disorder affecting        growth (e.g., hypothyroidism, premature adrenarche)    -   9. History of drug abuse within the last 3 years or habitual        alcohol consumption (defined as >1 ounce [28 g] of liquor or        4-ounce glass [113 g] of wine, or the equivalent, ≥3 times per        week)    -   10. Life expectancy predicted to be <5 years    -   11. History of a non-skin malignancy (with the exception of        cervical cancer in situ) within 3 years prior to enrolment    -   12. Treatment with any Investigational Medicinal Product (IMP)        within 6 months or 5 times the terminal half-life of the        corresponding IMP, whichever is longer, before the screening        visit    -   13. Patient is a dependent of the sponsor, of the        investigational team or his/her immediate family    -   14. Pregnant or nursing women

Outcomes

The primary efficacy endpoint is:

Percent change in LDL-C at Week 24±3 days compared to Baseline

Secondary Endpoints

The secondary efficacy endpoints of this study are:

-   -   Percent change from Baseline at Week 24±3 days for the following        lipid parameters: TC, Non-HDL-C, VLDL-C, TG, Lp(a), and apo B    -   Percent change from Baseline at all other time points through        Week 104±1 week for the following lipid parameters: LDL-C, TC,        Non-HDL-C, VLDL-C, TG, Lp(a), and apoB    -   Change in LLT and LA from Week 24±3 days through Week 104±1 week    -   Total number and percent of patients achieving the EAS        recommended target LDL-C of <135 mg/dL (3.5 mmol/L) in pediatric        HoFH patients at Week 24±3 days and at any time on study

Statistical Methods

The key efficacy and safety analyses are conducted once all patientshave completed or withdrawn prior to Visit 10 at Week 24±3 days (End ofthe Efficacy Phase) upon entry and cleaning of all data including Visit10 in order to allow for an early submission of an application forregulatory approval of Lojuxta® in the pediatric indication. Alldescriptive statistics of the efficacy parameters and all analyses ofsafety data collected during the Safety Phase are performed after alldata up to the FU Visit 23 (Week 108) has been entered and cleaned(including AE and concomitant medication data with date of onset untilFU visit [Week 108]).

Study Medications

Formulation, Packaging and Labelling

The investigational product is supplied in high-density polyethylenebottles with polyester, aluminium foil, and cardboard induction sealsand child-resistant polypropylene screw caps. It is packed and labelledaccording to applicable regulatory requirements.

Lomitapide is prepared as a crystalline methanesulfonate salt. Theinvestigational product is administered orally in opaque, hard gelatincapsules. Four bottle types contain 28 capsules each by 2 mg, 5 mg, 10mg, and 20 mg strength. Each hard capsule contains lomitapide mesylateequivalent to the labeled content of the free-base form of lomitapide,and the following inactive excipients: pregelatinised starch (maize),sodium starch glycolate (Type A), microcrystalline cellulose, lactosemonohydrate, colloidal, anhydrous silica, and magnesium stearate.

Drug and Dietary Supplements Accountability

A sufficient number of lomitapide bottles are provided to sites in bulkat appropriate intervals depending on the phase of the study and accrualof patients. Dietary supplements are sourced locally, where possible.The investigator, or the person designated by the investigator, areresponsible for dispensing the appropriate bottle or combination ofbottles to a patient at each study visit. At each site, theinvestigator, or the person designated by the investigator, isresponsible for keeping accurate records of study medicationaccountability comprising the receipt, the dispensing, and the return ofall used and partially unused study medication throughout the study. Thedrug accountability form is kept up to date and will be reviewedperiodically by the study monitor. Patients are asked to keep all usedand partially unused bottles of study medication and return them to thesite during the scheduled visits. For drug accountability, the number ofused and partially unused bottles and unused capsules are counted.Compliance with dietary supplements is discussed with the patients ateach visit and is documented in the electronic Case Report Form (eCRF).It is also verified by reviewing the patient Diet Records. After drugaccountability is completed, all unused or partially used studymedication are returned to the sponsor or disposed of by the study site.The study monitor instructs the site on the return of all studymedication. A final inventory of the total amount of study medicationand dietary supplements at each study site against the amount used andreturned is recorded. Inventory records are readily available forinspection by the study monitor and/or auditor, and open to governmentinspection at any time.

Dietary Supplements

Patients are administered daily oral supplementation with vitamin E (200IU for patients 5 to 8 years of age, 400 IU for patients 9 to ≤17 yearsof age) and an EFA supplement containing approximately 200 mg linoleicacid, 210 mg ALA, 110 mg EPA, and 80 mg DHA. Dietary supplements isdispensed during Visit 3 at Week −3 to Week −2 (Run-in Compliance),during Visit 4 at DO (Baseline, Efficacy Phase), and at every visitthereafter until Visit 21 at Week 92±1 week.

Diet Instructions and Diet Records

The occurrence and severity of GI AEs associated with the use oflomitapide decreases in the presence of a low-fat diet. Patients startto follow a diet supplying <20% of energy from fat or <30 g fat,whichever is the lesser amount at Visit 2, the Start of the Run-inPeriod, and continue this diet until the EoT (and the LTE of this study,when applicable).

A dietitian provides dietary counselling to the patients and theirparents/legal guardians from Visit 2 (Start of the Run-in Period)through Visit 5 at Week 4±3 days. Patients and parents/legal guardiansare instructed on how to consume <20% energy from fat or <30 g fat,whichever is the lesser amount. Instructions include detailedinformation concerning the role of dietary fat and GI-related symptomsand patients are encouraged to pay special attention to foods they eatwhen/if they experience these symptoms. The dietitian reviews currenteating habits in order to minimize adverse events and address potentialadherence problems. The dietitian alsotailors to each patient's caloricneeds to ensure a healthy weight and normal growth is maintained.

The dietitian also reviews compliance with the diet and discusses anyissues or concerns the patient and his/her parents/legal guardians mayhave with the diet at Visit 3 (Week −3 to Week −2). The dietitianinforms patients and their parents/legal guardians to call him/her todiscuss over the phone or schedule a meeting to address any diet-relatedquestions or concerns any time during the study. Additional resourcespertaining to the diet are available to the dietitian and the patientand his/her parent/legal guardian.

Weight is measured using a consistent approach at Screening and at eachvisit after the Run-in Period (i.e., child/adolescent always weighed insame amount of clothing, either in underwear, hospital gowns or bysubtracting the weight of clothes). Patients of normal or below normalbody weight with weight loss >3% since the last visit are instructed bythe dietitian on how to increase caloric intake based on individualneeds. The standard recommended fat intake for children >2 years old isto follow a diet with <30% energy from fat, hence, decreasing dietaryfat intake to <20% or <30 g fat, whichever is the lesser amount shouldnot pose any risk to patients of any age that may be enrolled in thisstudy.

The investigator requests additional dietary counselling as clinicallyindicated. At the same visits, 2-Day Diet Records are given to thepatients and their parents/legal guardians.

In order to assess dietary compliance and to provide information forinterpreting possible GI AEs, patients are instructed to document allfood and beverages consumed periodically throughout the study, usingDiet Records. A 2-Day Diet Record is dispensed and returned from Visit 2(Start of the Run-in Period) through Visit 21 at Week 92±1 week.

When diet-related problems are noted during the study, e.g., weight lossor GI-related complaints such as diarrhoea, the patients are requestedto fill out additional Diet Records. Note that Diet Records collectedduring the Run-in Period are not analysed, but are used by the dietitianon site to assess compliance before beginning lomitapide treatment.

Patients treated with lomitapide and their parents/legal guardians areadvised of the potential risk of dehydration in relation to GI AEs andtake precautions to avoid fluid depletion.

Study Design

This is a single-arm, open-label, multi-centre phase III study toevaluate the efficacy and long-term safety of lomitapide in pediatricpatients with HoFH receiving stable LLT (including LA, when applicable).Each patient participates for up to 120 weeks (about 2.5 years) in thestudy (see FIG. 2 ).

The study consists of 5 periods (see FIG. 2 ):

-   -   1. Screening Period (starting at Week −12, i.e. ≤12 weeks prior        to Baseline for up to 6 weeks)    -   2. Stratified Enrolment and Start of Run-in Period (starting at        minimum at Week −6, i.e., 6 weeks prior to Baseline for a        minimum of 6 weeks):        -   Enrolment is stratified to ensure approximately equal            numbers of patients in the following age groups: 5 to 10            years, 11 to 15 years, and 16 to ≤17 years (with ≥8 patients            in any individual age group).        -   Patients are stabilised on current LLT (including LA, when            applicable) and established on a diet supplying <20% of            energy (calories) from fat or <30 g fat, whichever is the            lesser amount.        -   Daily supplementation with vitamin E (200 international            units [IU] for patients 5 to 8 years of age, 400 IU for            patients 9 to ≤17 years of age) and an EFA supplement            containing approximately 200 mg linoleic acid, 210 mg ALA,            110 mg EPA, and 80 mg DHA starting at Week −2    -   3. Efficacy Phase (starting at Baseline, i.e. Day [D] 0 for 24        weeks±3 days)        -   Approximately 45 pediatric patients with HoFH are treated            with lomitapide given orally, added to their current, stable            LLT (including LA, when applicable) established during the            Run-in Period        -   Assuming a withdrawal rate of approximately 33% by Week 24±3            days, this results in 30 evaluable patients at Week 24±3            days (with ≥8 patients in any individual age group).        -   After the stabilization of the patient on his/her current            MTD of LLT (including LA, when applicable) during the 6-week            Run-in Period, treatment with lomitapide is started as an            add-on therapy on DO of the Efficacy Phase.        -   Dosing is initiated at the recommended starting dose and            escalated to the maximum dose as applicable to the age            groups based upon safety and tolerability in addition to            LDL-C values.        -   The first dose of study medication is administered at the            study site on D0.        -   During the 24-week Efficacy Phase, patients are required to            remain on the stable LLT regimen (including LA, when            applicable) established during the 6-week Run-in Period    -   4. Safety Phase (starting at Week 24±3 days for 80±1 weeks)        -   Patients enter the 80-week Safety Phase after the Week 24±3            days assessments have been completed. Each patient continues            receiving the MTD of lomitapide he/she achieved during the            Efficacy Phase (unless criteria is met for reducing the            dose) for an additional 80±1 weeks in the Safety Phase.        -   When after Week 24±3 days, a patient has crossed over into            the next age category, the study medication is escalated to            the maximum dose applicable for the new age category. When            the patient tolerates this new dose for ≥4 weeks, then this            is considered the new MTD.        -   As necessary during the 80-week Safety Phase, the lomitapide            dose is reduced from the MTD due to tolerability or safety            issues, and the patient is re-challenged after a minimum            period of 4 weeks following dose reduction with a higher            dose of lomitapide once these issues resolve, but the dose            during the Safety Phase does not exceed the MTD established            during the Efficacy Phase.        -   Adjustments to background LLT (including LA, when            applicable) are allowed at the discretion of the            investigator.    -   5. Follow-up (starting at Week 104±1 week for 4 weeks) or        participation in the LTE of this study        -   At Week 104±1 week, eligible patients who complete the study            per protocol can enter the LTE of this study, pending            approval by appropriate ethics committees and regulatory            authorities. A separate Protocol Amendment is prepared            describing the LTE in detail. For patients who opt not to            participate in the LTE of this study or who are ineligible,            there is a 4-week Follow-up period during which study            medication is discontinued and patients remain on            concomitant LLT (including LA, when applicable)

Interventions

This is an open-label study, blinding of treatment is not applicable.

After the stabilization of the patient on his/her current MTD of LLT(including LA when applicable) during the 6-week Run-in Period,treatment with lomitapide is started as add-on therapy on DO of theEfficacy Phase.

Lomitapide capsules is provided in 4 dose strengths of 2 mg, 5 mg, 10mg, and 20 mg. Dosing is initiated at the recommended starting dose andescalated to the maximum dose as applicable to the age groups (see Table1 and FIG. 2 ) based upon safety and tolerability in addition to LDL-Cvalues.

TABLE 1 Lomitapide Starting Dose and Dose Escalation by Age GroupLomitapide Dose (mg) Age Week Week Week Week Group 4 ± 8 ± 12 ± 16 ±(years) D 0 3 days 3 days 3 days 3 days Maximum 5 to 10 2 2 5 10 20 20(10, in Child-Pugh A) 11 to 15 2 5 10 20 40 40 (20, in Child-Pugh A) 16to ≤17 5 10 20 40 60 60 (40, in Child-Pugh A)

Each patient takes 1 to 3 capsule(s) once daily to achieve the dosesspecified in the titration scheme. The first dose of study medication isadministered at the study site on DO.

As of D1, patients self-administer (or the patient's parent/legalguardian administers to the patient) lomitapide orally, once daily, atapproximately the same time each day. Ideally, lomitapide isadministered at least 2 hours after the evening meal (e.g., at bedtime)with a glass of water on an empty stomach because the fat content of arecent meal may adversely impact GI tolerability. Patients who areunable to swallow the intact capsule(s) open the capsule(s) and sprinklethe capsule content on 1 tablespoon of apple sauce or mashed banana,which are fat-free.

In case of a missed dose, patients are instructed to take missed dosesof lomitapide only if they can be taken at least 12 hours prior to thenext scheduled dose. Dietary supplements are ideally taken in themorning. Patients taking bile acid sequestrants are reminded that theyshould take lomitapide 4 hours before or 4 hours after this class ofmedications. If atorvastatin is given concomitantly, lomitapide isadministered 12 hours apart.

What is claimed:
 1. A method of safely administering lomitapide, or apharmaceutically acceptable salt thereof, to a pediatric patientcomprising: (a) administering a first daily dose of about 0.5 mg toabout 2.5 mg of lomitapide, or a pharmaceutically acceptable saltthereof to a patient aged 5 to 15 years; and (b) administering a firstdaily dose of about 2.5 mg to about 7.5 mg of lomitapide, or apharmaceutically acceptable salt thereof to a patient aged 16 to 17years, wherein the first daily dose is administered to the patient forabout 1 to 4 weeks.
 2. A method of treating hyperlipidemia orhypercholesterolemia in a pediatric patient, comprising: (a)administering an first daily dose of about 0.5 mg to about 2.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof to a patient'sage is 5 to 15 years; (b) administering a first daily dose of about 2.5mg to about 7.5 mg of lomitapide, or a pharmaceutically acceptable saltthereof to a patient's age is 16 to 17 years, wherein the first dailydose is administered to the patient for about 1 to 4 weeks.
 3. A methodof treating hyperlipidemia or hypercholesterolemia, comprising:administering a first daily dose of about 0.5 mg to about 2.5 mg oflomitapide, or a pharmaceutically acceptable salt thereof to a pediatricpatient age 5 to 10 years, wherein the first daily dose is administeredto the patient for about 1 to 4 weeks.
 4. A method of treatinghyperlipidemia or hypercholesterolemia, comprising: administering afirst daily dose of about 0.5 mg to about 2.5 mg of lomitapide, or apharmaceutically acceptable salt thereof to a pediatric patient age 11to 15 years, wherein the first daily dose is adminstered to the patientfor about 1 to 4 weeks.
 5. A method of treating hyperlipidemia orhypercholesterolemia, comprising: administering a first daily dose ofabout 2.5 mg to about 7.5 mg of lomitapide, or a pharmaceuticallyacceptable salt thereof to a pediatric patient age 16 to 17 years,wherein the first daily dose is administered to the patient for about 1to 4 weeks.
 6. The method of any one of claims 1-5, wherein the firstdaily dose is administered to the patient for about 4 weeks.
 7. Themethod of any one of claims 1-6, wherein the patient has homozygousfamilial hypercholesterolemia.